Process for the preparation of 3, 12-dihydroxy cholenic acids and their esters



Patented Feb. 16, I954 2,669,571 PROCESS FOR THE PR DIHYDROXY CHOLEESTERS Temple Clayton,

EPARATION OF 3,12- NIC ACIDS AND THEIR Parsippany, Emanuel B. Hershberg, West Orange, and Bernard F. Schoen,

Union City, N. ration, Jersey J., assignors to Schering Corpo-Bloomfield, N. J., a corporation of New No Drawing. Application August25, 1950, Serial No. 181,568

22 Claims. (Cl. 260397.1)

The present invention relates to a process for eliminating selenium fromunsaturated keto steroid acids and their esters which have been preparedby the action of selenium dioxide or selenious acid on the correspondingsaturated keto acids and their esters, and more particularly to theelimination of selenium from unsaturated A 12-keto steroid acids andtheir esters produced by the dehydrogenation of the saturated compoundswith selenium dioxide or selenious acid.

While our invention is of general application to the de-contamination ofunsaturated steroid ketones prepared with the aid of selenium compounds,it will be described in detail below in connection with the treatment ofA -12-keto-17- steroid acids and their esters preparatory to orsimultaneously with the further chemical modification of such steroids,as by reduction, for the preparation of intermediates for themanufacture of cortisone.

In the dehydrogenation of 3-hydroxy l2-keto cholanic acids and theiresters (wherein the 3- hydroxyl group is protected in known manner byetherification or esterification, for example by succinylation) with theaid of selenium dioxide or selenious acid, the resulting unsaturatedcompound has selenium attached thereto so tenaciously that it isdifiicult to remove it in the usual ways. The presence of the seleniumis objectionable not only because it contaminates the product but alsobecause it interferes with subsequent reactions, such as reduction andother chemical processes, and seriously affects the yields of theseprocesses.

Thus in the reactions described in the cbpending application of ErwinSchwenk, Serial No. 754,278, filed June 12, 1947, now Patent No.2,581,448, various 3-acyloxy 12-keto cholanic acids, including the nor-,bisnorand etiocholanic acids, are heated with selenious acid in aceticacid solution to effect dehydrogenation at the 9,11-carbons. Theresulting unsaturated keto acids contain a considerable proportion ofthe selenium originally employed and the same cannot be removed byrepeated attempts at purification by re-solution and crystallization.When these products are employed as intermediates for the manufacture ofother steroid compounds, such as the A -12-hydroxy cholanic acid or itsesters, for the manufacture of further intermediates in the preparationof cortisone, the contaminating selenium persists in the product andgreatly reduces the yields.

We have found that the contaminating selenium can be removed from thesteroid compound by treating a solution of the latter with Raney nickelcatalyst. The treatment may be effected by heating the solution withHaney nickel, which binds the selenium, and upon separation of thesolution from the catalyst, a product is obtained which is free fromselenium and can be subjected to any desired further treatment. Toinsure the removal of all of the selenium within a reasonably shorttime, the quantity of nickel employed for the removal of the seleniummay be of the order of half the weight of the steroid compound and evenmore. It is of advantage to employ a quantity of catalyst which is onehalf to two or more times the Weight of the steroid to be reduced. Insuch case, it is not necessary to separate the nickel containing theselenium until after the reduction. By proceeding in this manner, thereduced product is recovered in a very nearly water-white solution.

Where the steroid is to be subjected to hydrogenation by means of Raneynickel-aluminium alloy in alkali metal hydroxide solution, theelimination of the selenium and hydrogenation of the steroid can takeplace in one step, and in such case a quantity of alloy much in excessof the weight of the steroid compound, desirably of the order of fourtimes the weight of the latter, is employed. The hydrogenation andsimultaneous purification of the l2-keto compound can, however, also beaccomplished with activated Haney nickel and molecular hydrogen. Thusthe removal of the selenium can be effected while the steroid is beingsubjected to reduction with either nascent or molecular hydrogen.

The starting steroids can be any of those produced by the processdescribed in the above named application, or they can be any stereoidswhich have been subjected to dehydrogenation by means of seleniumdioxide or selenious acid.

It will be understood that while the removal of the selenium is eiiectedby means of Raney nickel catalyst, the hydrogenation oi the purifiedintermediate can be efiected in the presence of other hydrogenationcatalysts.

The invention will be further described with the aid of the followingexamples which are presented for illustrative purposes only.

EXAMPLE I Methyl-19: -3,12-dihydroa:y cholenate toxification-catalyst,the solution was diluted to 6 l. with methanol and 900 g. fresh nickelcatalyst added and the ester reduced under hydrogen. Hydrogenationproceeded smoothly and hydrogen absorption substantially ceased in 3hours. After removal of the catalyst by filtration, the product wasconverted in known manner to the 12-methYl ether (melting at 157 C.) forisolation.

EXAMPLE II A -3,12-dz'hydromy cholenic acid To a solution of 50 g. A-3-hydroxy-12-keto cholenic acid in 300 g. sodium hydroxide and 7.0 1.water, 30 g. portions of Raney nickel-aluminium alloy were added atintervals until a total of 210 g. had been added over about 3hours. Thecourse of the reduction was followed by determining the ultra-violetabsorption of thesolution between 215 and 280 m The absorption due tothe apt-unsaturated ketone disappeared gradually as the carbonyl groupwas reduced. After filtering ofi the precipitated nickel, the solutionwas acidified and the reduced acid was collected. Without furtherpurification, it was converted tomethyl-3,9epoxy-11,12-dibromo-cholanate melting at 135-140 C. by theknown sequence of reactions (Kendall et al., J. Biol. Chem. 1'73, 2'71(1948), and 164, 569 (1946)).

EXANLPLE III M ethyl-A 3,1 2- dihydroxycholenate 402 g. methyl-A-3-hydroxy-1Z-ketocholenate containing selenium as an impurity weredissolved. in. 2 l. methanol in a small. hydrogenator and to it wereadded 800 g. activated Raney nickel catalyst, which was worked in withafurther 2 l. of methanol. Hydrogen was introduced and absorbed readilyand at the end of 90 minutes the reaction was substantially complete.The solution of methyl-A -3,12-dihydroxycholenate was converted in theknown manner to the 12-methyl ether for isolation.

As already indicated the actual reduction of the purified keto acids ortheir esters can be accomplished by methods other than by the use ofRaney catalysts provided, of course, that the nuclear double bond is notsimultaneously reduced. Although the B-hydroxy group in the aboveexamples is free, it may be replaced by a methoxy, ethoxy, acetoxy,succinoxy or other ether, acyloxy or other radical from which thehydroxyl group canbe' regenerated with the aid of hydrolysis. Also, asmentioned above, the purification process can be applied to othersteroid acids and their esters, including the 17-degration products ofthe cholenic acids, which. may or may not be nuclearly substituted asdisclosed in the above examples.

We claim:

1. Process for the removal of selenium from the selenium-contaminateddehydrogenated product of the reaction of a member of the groupconsisting of selenium dioxide and selenious acid on a keto steroid,comprising subjecting a solution of such contaminated product to theaction of a Raney nickel catalyst until separation of the selenium fromsaid product has been efiected'.

2. Process for the removal of selenium from the selenium-contaminateddehydrogenation product of the reaction of a member of the groupconsisting of selenium dioxide and selenious acid on a keto steroid withsimultaneous reduction of the keto group, which comprises subjecting asolution of said contaminated steroid to the action of a Raney nickelcatalyst and a member of the group 75- molecular hydrogen in comprisingmolecular and nascent hydrogen until substantially completehydrogenation of the keto group to the hydroxyl group has been effected.

3'. Process for the removal of selenium from the selenium-contaminateddehydrogenated product of the reaction of a member of the groupconsisting of selenium dioxide and selenious acid on a keto steroid,comprising refluxing a solution of such product in a lower aliphaticalcohol with a Raney nickel catalyst until separation of the seleniumfrom said product has been effected.

4. Process for the removal of selenium from the selenium-contaminateddehydrogenated product of the reaction of a member of the group consisting of selenium dioxide and selenious acid on a keto steroid;-comprising refluxing a solution of such product in a lower aliphaticalcohol with approximately half its weight of a Raney nickel catalystfor about 16 hours, and separating the solid matter containing theselenium.

5. Process for removal selenium-contaminated dehydrogenated product ofthe reaction of a member of the group consisting of selenium dioxide andselenious acid on a compound or" the group consisting of 3-hydroxy-12-keto cholanic acids and their esters, comprising subjecting a actionof a Raney nickel catalyst until separation of the selenium from saidproduct has been effected.

6. Process for the reduction of selenium-containing 12-keto steroids toproduce the corresponding lz-hydroxy compound free from selenium, whichcomprises heating a solution of the steroid with Rane-y nickel catalystto effect removal of the selenium, and thereafter subjecting the steroidto the action of a reducing agent of the group consisting of nascenthydrogen and the presence of a hydrogenation' catalyst.

7. Process for the reduction of selenium-containing l2-keto steroids toproduce the corresponding 12-hydroxy compound free from sele nium, whichcomprises heating a solution of the steroid with Raney nickel catalystto effect re-- moval' of the selenium, filtering off the catalyst, andthen subjecting the solution to the action of molecular hydrogen in thepresence of fresh nickel catalyst.

8. Process according to claim '7 wherein the solvent is a loweraliphatic alcohol.

9. Process for thereduction of selenium-containing 12-keto steroids toproduce the corresponding 12-hyd'roxy compound. free from sole-- nium,which comprises reacting a solution of the steroid in an alkali metalhydroxide solution with a Raney nickel-aluminium alloy, and removing"the metallic residue after the 12-keto grouphas been reduced.

10-. Process according to claim 9, wherein the" taining methyl A-3-hydroxy-I2keto chol'enate to selenium free methyl A 3,12 dihydroxycholenate, comprising heating a solution of the 12-keto compound with aRaney' nickel catalyst;

separating the solution from the selenium-containing catalyst, andsubsequently hydrogenating the 12-keto group to the hydroxyl group.

12. Process according to claim 11, whereinthe hydrogenation of the12-keto group iseffected. by

reaction with hydrogen in the presence of Raney nickel catalyst.

13. Process for the reduction of selenium-conof selenium from thesolution of such product to the taining A -3-hydroxy-l2-keto cholenicacid to selenium-free A -3,12-dihydroxy cholenic acid which comprisesheating a solution'of the 12-keto compound in an alkali metal hydroxidesolution with an excess of Raney nickel-aluminium alloy, and separatingthe solution of the 3,12-dihydroxy compound from the selenium-containingcatalyst.

14. Process according to claim 13, wherein the nickel-aluminium alloy isadded in portions.

15. Process according to claim 13, wherein the ratio of nickel-aluminiumalloy to the 12-keto compound is of the order of 4 to 1.

16. Process according to claim 1, wherein the weight of nickel catalystis at least half that of the selenium-containing product.

17. Process according to claim 7, wherein the total amount of nickelcatalyst is in excess of the weight of the selenium-containing steroid.

18. Process for the removal of selenium from the selenium contaminateddehydrogenated product of the reaction of a member of the groupconsisting of selenium dioxide and selenious acid on methyl3-hydroxy-12-keto cholanate, comprising subjecting a solution of suchproduct to the action of a Raney nickel catalyst until separation of theselenium from said product has been effected.

19. Process according to claim 2, wherein the quantity of catalyst isapproximately twice that of the steroid.

20. Process according to claim 2, wherein the steroid is a member of thegroup consisting of A -3-hydroxy-12-keto-cholenic acids and theiresters.

21. Process for the removal of selenium from the selenium contaminateddehydrogenated product of the reaction of a member of the groupconsisting of selenium dioxide and selenious acid on steroid compounds,which comprises subjecting a solution of such selenium-contaminateddehydrogenated steroid compound to the action of a Raney nickel catalystuntil separation of the selenium from said compound has been effected.

22. Process according to claim 21, wherein the steroid compound containsa reducible carbonyl group, and wherein reduction of the keto group toan alcohol group is effected with hydrogen simultaneously with theremoval of the contaminating selenium.

TEMPLE CLAYTON. EMANUEL B. HERSHBERG. BERNARD F. SCHOEN.

N 0 references cited.

1. THE PROCESS FOR THE REMOVAL OF SELENIUM FROM THESELENIUM-CONTAMINATED DEHYDROGENATED PRODUCT OF THE REACTION OF A MEMBEROF THE GROUP CONSISTING OF SELENIUM DIOXIDE AND SELENIOUS ACID ON A KETOSTERIOD, COMPRISING SUBJECTING A SOLUTION OF SUCH CONTAMINATED PRODUCTTO THE ACTION OF A RANEY NICKEL CATALYST UNTIL SEPARATION OF THESELENIUM FROM SAID PRODUCT HAS BEEN EFFECTED.